Influence of PAX6 Gene Dosage on Development: Overexpression Causes Severe Eye Abnormalities

Schedl, Andreas; Ross, Allyson; Lee, Muriel; Engelkamp, Dieter; Rashbass, Penny; Heyningen, Veronica van; Hastie, Nicholas D.

doi:10.1016/s0092-8674(00)80078-1

Cited by 400 publications

(325 citation statements)

References 40 publications

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“…Pax6 is upstream of Sox2 (Furuta and Hogan, 1998), Pax6 and Sox2 cooperatively regulate gene expression (Kamachi et al 2001, Aota et al, 2003, and Sox2 is required for the maintenance of Pax6 (Donner et al, in press). Appropriate temporal, spatial, and quantitative control of Pax6 expression is required for appropriate lens morphogenesis (Hill et al, 1991;Glaser et al, 1994;Hanson et al, 1994;Grindley et al, 1995;Quinn et al, 1996;Schedl et al, 1996;Brown et al, 1998;Ashery-Padan et al, 2000;Duncan et al, 2000;van Raamsdonk and Tilgham, 2000;Dimanlig et al, 2001;Duncan et al, 2004). PAX6 mutation is causative for several congenital eye defects in humans including aniridia, Peters' anomaly and cataract (reviewed in Prosser and van Heyningen, 1998).…”

Section: Resultsmentioning

confidence: 99%

Pax6 is misexpressed in Sox1 null lens fiber cells

Donner

Episkopou

et al. 2007

Gene Expression Patterns

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Sox1 null lens fiber cells fail to elongate and have disrupted expression of gamma crystallin. We have evaluated the expression of Sox1 and Pax6 proteins during critical stages of lens morphogenesis, with particular focus on fiber cell differentiation. While Pax6 and Sox1 are co-expressed during early stages of fiber cell differentiation, Sox1 up-regulation coincides temporally with the down-regulation of Pax6, and these proteins therefore display a striking inverse expression pattern in the lens fiber cell compartment. Furthermore, Pax6 is inappropriately expressed in the fiber cells of Sox1 null mice and the Pax6 target, α5 integrin, is simultaneously misexpressed. Finally, we demonstrate a genetic interaction between Sox1 and Pax6, as Sox1 heterozygosity partially rescues the diameter of Pax6 Sey lenses by increasing the number of cells in the fiber cell compartment.

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Section: Resultsmentioning

confidence: 99%

Pax6 is misexpressed in Sox1 null lens fiber cells

Donner

Episkopou

et al. 2007

Gene Expression Patterns

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“…This dose-response analysis revealed that the increase of ␣ cells and of glucagon transcripts was maximal with 1.5 ng of injected Mo2 corresponding to a mild reduction of pax6b activity. Previous studies have shown that a precise range of the Pax6 protein level is important for the proper development of the eyes, brain, and pancreas because an increase of Pax6 expression in transgenic mice leads to abnormalities in these organs (19,20,34). Moreover, heterozygous Pax6 individuals display anomalies in eye morphology and brain patterning (10).…”

Section: Discussionmentioning

confidence: 99%

The Pax6b Homeodomain Is Dispensable for Pancreatic Endocrine Cell Differentiation in Zebrafish

Verbruggen

Georlette

et al. 2010

Journal of Biological Chemistry

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Pax6 is a well conserved transcription factor that contains two DNA-binding domains, a paired domain and a homeodomain, and plays a key role in the development of eye, brain, and pancreas in vertebrates. The recent identification of the zebrafish sunrise mutant, harboring a mutation in the pax6b homeobox and presenting eye abnormalities but no obvious pancreatic defects, raised a question about the role of pax6b in zebrafish pancreas. We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. Pax6b-depleted embryos have almost no ␤ cells, a strongly reduced number of ␦ cells, and a significant increase of ⑀ cells. Through the use of various morpholinos targeting intron-exon junctions, pax6b RNA splicing was perturbed at several sites, leading either to retention of intronic sequences or to deletion of exonic sequences in the pax6b transcript. By this strategy, we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. These data thus provide the explanation for the lack of pancreatic defects in the sunrise pax6b mutants. In addition, partial reduction of Pax6b function in zebrafish embryos performed by injection of small amounts of pax6b morpholinos caused a clear rise in ␣ cell number and in glucagon expression, emphasizing the importance of the fine tuning of the Pax6b level to its biological activity.

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“…Therefore, overexpression of Pa 6 was shown to disturb the normal development of beta cells. In the development of eyes, overexpression of Pa 6 in transgenic mice was also reported to cause severe microphthalmia although appropriate expression of Pa 6 rescued eye abnormalities observed in Small eye mice which have mutations in the Pa 6 gene [22].…”

Section: Discussionmentioning

confidence: 99%